The novel compound TDN-345 induces synthesis/secretion of nerve growth factor in C6-10A glioma cells.
A novel compound, TDN-345, not bearing catechol moiety, induced NGF synthesis/secretion in C6-10A glioma cells. Both intracellular and extracellular nerve growth factor (NGF) protein levels increased within 3 h and reached a maximum around 12 h after the addition of TDN-345. The induction of NGF synthesis/secretion by TDN-345 occurred in a concentration-dependent manner, beginning with about 0.1 microM and reaching a maximum at 10 microM. The ED50 was 0.88 microM. The induction was accompanied by an increase in NGF mRNA but not beta-actin mRNA. In a time-course study, the NGF mRNA level was found to reach a maximum 2-3 h after the addition of TDN-345 and then to return to control levels. The induction occurred dose-dependently. The catecholaminergic compound epinephrine, which induces NGF synthesis/secretion, increased the intracellular cyclic AMP content by more than 1000-times at 10 microM. In contrast, TDN-345 did not cause such a prominent increase in cAMP even at 100 microM. These results indicate that TDN-345 induces NGF synthesis/secretion by increasing NGF mRNA expression, and the action of TDN-345 clearly differs from that of epinephrine, as it does not seem to involve cAMP as a second messenger. The results of the present study suggest the existence of a signal transduction pathway for NGF synthesis/secretion which is not mediated by cAMP.
Fukumoto
H
H
Pharmaceutical Research Laboratories I, Takeda Chemical Ind. Ltd., Osaka, Japan. fukumoto_hiroaki@takeda.co.jp
Kakihana
M
M
Kaisho
Y
Y
Suno
M
M
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D007425:Intracellular Membranes / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D009414:Nerve Growth Factors; D012333:RNA, Messenger; D013141:Spiro Compounds; C108126:TDN 345; D000242:Cyclic AMP; D004837:Epinephrine